The success of anti-retroviral therapy (ART) has led to an increased number of HIV-infected individuals experiencing complicated chronic non-infectious diseases including HIV-Associated Nephropathy (HIVAN) and subsequent End Stage Renal Disease (ESRD). Although renal transplantation is the most favorable and often only treatment option, the probability of dying on the waiting list for a healthy organ is higher than te probability of receiving one. The use of HIV-infected Deceased Donors (HIVDD) as a novel source of kidneys could alleviate the organ shortage. South Africa is the only country globally doing HIVDD kidney transplantation to HIV infected recipients, and the US is considering this option. Hence there is a need to evaluate the efficacy and safety of HIV- infected-to-HIV-infected organ transplantation. In this application we will study the only population of HIV-positive to positive transplant patients in the world in order to identify virological factors that underlie the re-emergence of HIVAN after transplantation. To this end we will first determine the incidence, extent, and nature of donor-to- recipient HIV-superinfection using drug resistance testing, digital droplet PCR, and two distinct next- generation sequencing techniques. Secondly we will quantify recipient's virus infiltration into the graft kidney and investigate virus compartmentalization in the kidney epithelium using laser directed microdissection. And finally we will investigate whether these and other factors are associated with re- emergence of HIVAN in HIV-infected-to-HIV-infected recipients. The results of this study will have a direct and immediate influence on transplant clinical practice in South Africa and on clinical decisions and policy in the US as was called for in the US landmark HIV Organ Policy Equity (HOPE) Act in November 2013. Additionally, our study provides an opportunity to answer multiple fundamental biological questions surrounding HIV-SI, viral infiltration into tissues, the role of minor ART resistance for future care, and factors that influence establishment of tissue specific viral reservoirs, which would be informative for HIV cure research.